Project Summary/Abstract Despite significant advances in secondary prevention, recurrent myocardial infarction (MI) remains a major cause of morbidity and mortality. In the U.S., nearly 1 million adults have an MI each year, approximately 1/3 of which are recurrent. Patients surviving their first MI are at a high risk of recurrent events. In those who do develop recurrent MI, the annual mortality rate increases to 10%, two-fold higher than after their first MI. While much work has been done to identify common genetic variation for incident coronary artery disease, there is a large gap in the literature as to what variants contribute to recurrent MI. While overlap likely exists, there are distinct biological features between the development of atherosclerosis and recurrent MI. In Dr. Marston?s preliminary work, he tested a validated incident CAD genome-wide polygenic risk score in a post-MI population and found that it did not predict recurrent MI. This finding formed his central hypothesis that genetic predictors for recurrent MI differ from those that predict incident CAD. Until recently, datasets did not exist to test this hypothesis. However, large amounts of genotyped and sequenced data from randomized clinical trials in post-MI patients are now available, allowing both discovery and clinical application of germline and somatic mutations associated with recurrent MI. In this proposal, Dr. Marston will leverage 9 cardiovascular clinical trials from the TIMI Study Group to test his hypothesis in three specific aims. First, Dr. Marston will define the role of common genetic variation and develop a polygenic risk score for predicting recurrent MI using 14K cases of recurrent MI and 69K MI controls. Novel variants for recurrent MI will be identified through large-scale genome-wide association studies and validated for their ability to predict risk in patients following their first MI. Second, Dr. Marston will determine whether rare genetic variation or clonal hematopoiesis is associated with recurrent MI using exome sequencing data in 9K recurrent MI cases and 39K MI controls. Third, Dr. Marston will use randomized clinical trial data to test for gene x treatment interactions across 5 secondary prevention therapies with a polygenic risk score and across 2 secondary prevention therapies with CHIP. The presence of a gene x treatment interaction can be used to inform therapeutic decision making and tailored therapy. This work will take place in the Division of Cardiovascular Medicine at Brigham and Women?s Hospital, a core teaching hospital of Harvard Medical School. Dr. Marston will perform the research under the mentorship of Dr. Marc Sabatine, Chairman of the TIMI Study Group, and Dr. Patrick Ellinor, Director of the Cardiovascular Disease Initiative at the Broad Institute. Dr. Marston?s goal is to become a genetic epidemiologist and clinical trialist with the ability to build large important datasets and use state of the art computational approaches to identify novel insights into the prevention and treatment of CAD. He is dedicated to becoming an independent investigator and using his K08 work as a foundation for an R01, in which he will apply genetic risk markers to improve clinical trial design and optimize precision in cardiovascular care.